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General Information About Childhood Astrocytomas

Primary brain tumors, including astrocytomas, are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification.

Gliomas are thought to arise from glial precursor cells that are present in the brain and spinal cord. Gliomas are named according to their clinicopathologic and histologic subtype. For example, astrocytomas originate from astrocytes, oligodendroglial tumors from oligodendrocytes, and mixed gliomas from a mix of oligodendrocytes, astrocytes, and ependymal cells. Astrocytoma is the most commonly diagnosed type of glioma in children.

According to the World Health Organization (WHO) classification of brain tumors, gliomas are classified further as low-grade (grades I and II) or high-grade (grades III and IV) tumors. Children with low-grade tumors have a relatively favorable prognosis, especially when the tumors can be completely resected. Children with high-grade tumors generally have a less favorable prognosis, but this is somewhat dependent on subtype.

The PDQ childhood brain tumor treatment summaries are organized primarily according to the WHO classification of nervous system tumors.[1 ,2 ] For a full description of the classification of nervous system tumors and a link to the corresponding treatment summary for each type of brain tumor, refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors Treatment Overview.

Anatomy

Childhood astrocytomas can occur anywhere in the central nervous system (CNS) (refer to Figure). Refer to Table 3 for the most common CNS location for each tumor type. Anatomy of the inside of the brain, showing the cerebrum, cerebellum, brain stem, spinal cord, optic nerve, hypothalamus, and other parts of the brain.

Clinical Features

Presenting symptoms for childhood astrocytomas depend on the following:

CNS location.

Size of the tumor.

Rate of tumor growth.

Chronologic and developmental age of the child.

In infants and young children, low-grade astrocytomas presenting in the hypothalamus may result in diencephalic syndrome, which is manifested by failure to thrive in an emaciated, seemingly euphoric child. Such children may have little in the way of other neurologic findings, but can have macrocephaly, intermittent lethargy, and visual impairment.[3 ]

Diagnostic Evaluation

The diagnostic evaluation for astrocytoma is often limited to a magnetic resonance imaging (MRI) of the brain or spine. Spinal MRI is sometimes performed in conjunction with the initial brain MRI to exclude neuraxis metastases.

Computed tomography (CT) scans and positron emission tomography (PET) scans are not typically used for characterization of suspected gliomas. Similarly, lumbar punctures examining the cerebrospinal fluid for circulating tumor cells are not commonly performed in children with this disease.

Clinicopathologic Classification of Childhood Astrocytomas and Other Tumors of Glial Origin

The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Examination of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.

According to the WHO histologic typing of CNS tumors, childhood astrocytomas and other tumors of glial origin are classified according to clinicopathologic and histologic subtype and are graded (grade I to IV).[1 ]

WHO histologic grades are commonly referred to as low-grade gliomas or high-grade gliomas (refer to Table 1).

Table 1. World Health Organization (WHO) Histologic Grade and Corresponding Classification for Tumors of the Central Nervous System

WHO Histologic Grade

Grade Classification

I

Low grade

II

Low grade

III

High grade

IV

High grade

The 2016 WHO criteria began to utilize molecular data in the diagnosis of some tumors because of the accumulation of published evidence supporting that tumor behavior is typically driven by common biological alterations (refer to Table 2). Within glial CNS tumors, this was most evident in changes in the classification of the diffuse gliomas, which were grouped together based on genetic driver mutations rather than histopathological similarities.[2 ] Two diffuse gliomas are no longer considered distinct entities: fibrillary astrocytoma and protoplasmic astrocytoma. Epithelioid glioblastoma is a new, provisionally included variant that is categorized as one subtype of IDH-wildtype glioblastoma.

b In 2007, the WHO determined that the pilomyxoid variant of pilocytic astrocytoma may be an aggressive variant that is more likely to disseminate, and it was reclassified as a grade II tumor.[1 ,2 ,4 ]In 2016, the WHO suggested not grading the pilomyxoid variant until further studies clarify their behavior.[2 ]

Diffuse Astrocytic Tumors:

-Diffuse astrocytoma,IDH-mutant

II

-Anaplastic astrocytoma,IDH-mutant

III

-Glioblastoma,IDH-wildtype

IV

-Glioblastoma,IDH-mutant

IV

-Diffuse midline glioma,H3K27M-mutant

IV

Other Astrocytic Tumors:

-Pilocytic astrocytoma

I

-Pilomyxoid astrocytoma

Grade uncertainb

-Pleomorphic xanthoastrocytoma

II

-Anaplastic pleomorphic xanthoastrocytoma

III

-Subependymal giant cell astrocytoma

I

Other Gliomas:

-Angiocentric glioma

I

-Choroid glioma of the third ventricle

II

-Astroblastoma

Grade uncertainb

CNS location

Childhood astrocytomas and other tumors of glial origin can occur anywhere in the CNS, although each tumor type tends to have common CNS locations (refer to Table 3).

Table 3. Common Central Nervous System (CNS) Locations for Childhood Astrocytomas and Other Tumors of Glial Origin

More than 80% of astrocytomas located in the cerebellum are low grade (pilocytic grade I) and often cystic; most of the remainder are diffuse grade II astrocytomas. Malignant astrocytomas in the cerebellum are rare.[1 ,2 ] The presence of certain histologic features (e.g., MIB-1 rate, anaplasia) has been used retrospectively to predict event-free survival for pilocytic astrocytomas arising in the cerebellum or other location.[5 ,6 ,7 ]

Astrocytomas arising in the brain stem may be either high grade or low grade, with the frequency of either type being highly dependent on the location of the tumor within the brain stem.[8 ,9 ] Tumors not involving the pons are overwhelmingly low-grade gliomas (e.g., tectal gliomas of the midbrain), whereas tumors located exclusively in the pons without exophytic components are largely high-grade gliomas (e.g., diffuse intrinsic pontine gliomas with the H3K27M-mutant genotype).[8 ,9 ] (Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for more information.)

High-grade astrocytomas are often locally invasive and extensive and tend to occur above the tentorium in the cerebrum.[10 ,11 ] Spread via the subarachnoid space may occur. Metastasis outside of the CNS has been reported but is extremely infrequent until multiple local relapses have occurred.

Gliomatosis cerebri is no longer considered a distinct entity, but rather to be a growth pattern found in some diffuse gliomas. However, this description encompasses widespread involvement of the cerebral hemispheres, often extending caudally to affect the brain stem, cerebellum, and/or spinal cord.[1 ] It rarely arises in the cerebellum and spreads rostrally.[12 ] The neoplastic cells are most commonly astrocytes, but in some cases, they are oligodendroglia. They may respond to treatment initially, but overall have a poor prognosis.[13 ]

Neurofibromatosis type 1 (NF1)

Children with NF1 have an increased propensity to develop WHO grade I and grade II astrocytomas in the visual (optic) pathway; approximately 20% of all patients with NF1 will develop an optic pathway glioma. In these patients, the tumor may be found on screening evaluations when the child is asymptomatic or has apparent static neurologic and/or visual deficits.

Pathologic confirmation is frequently not obtained in asymptomatic patients; when biopsies have been performed, these tumors have been found to be predominantly pilocytic (grade I) rather than diffuse higher-grade astrocytomas.[2 ,4 ,14 ,15 ,16 ]

In general, treatment is not required for incidental tumors found with surveillance neuroimaging. Symptomatic lesions or those that have radiographically progressed may require treatment.[17 ]

Tuberous sclerosis

Patients with tuberous sclerosis have a predilection for low-grade glioma development, especially subependymal giant cell astrocytomas.[18 ] Mutations in either TSC1 or TSC2 cause pathway alterations that impact the mammalian target of rapamycin (mTOR) pathway, leading to increases in proliferation. Subependymal giant cell astrocytomas have been sensitive to targeted approaches via inhibition of the mTOR pathway.[19 ]

Genomic Alterations

Low-grade gliomas

Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.

Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas.[29 ] However, other factors such as CDKN2A deletion, whole chromosome 7 gain, and tumor location may modify the impact of the BRAF mutation on outcome.[31 ]; [32 ][Level of evidence: 3iiiDiii] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.[33 ]

BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[28 ,29 ]

Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[21 ,23 ,24 ,34 ]BRAF V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytomas.[35 ,36 ,37 ] One retrospective study of 53 children with gangliogliomas demonstrated BRAF V600E staining in approximately 40% of tumors. Five-year recurrence-free survival was worse in the V600E-mutated tumors (about 60%) than in tumors that did not stain for V600E (about 80%).[38 ] Similarly, children with diencephalic low-grade astrocytomas with a BRAF V600E mutation had a 5-year PFS of 22%, compared with a 52% PFS in children who were BRAF wildtype.[39 ][Level of evidence: 3iiiDiii] The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of mutation in cases that did not transform (10 of 167 cases).[33 ]

Angiocentric gliomas have been noted to largely harbor MYB-QKI fusions, a putative driver mutation for this relatively rare class of gliomas.[40 ]

Activating mutations in FGFR1, PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[41 ] In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[42 ,43 ]

Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in activation of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules. Because subependymal giant cell astrocytomas are driven by mTOR activation, mTOR inhibitors are active agents that can induce tumor regression in children with these tumors.[44 ]

Pediatric high-grade gliomas have PTEN and EGFR genomic alterations less frequently and PDGF/PDGFR genomic alterations and mutations in histone genes (primarily histone 3.3 [H3F3A] but also histone 3.1 [HIST1H3B]) more frequently than do adult tumors.

Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have IDH1 and IDH2 mutations, the latter mutations are rarely observed in children younger than 15 years with high-grade gliomas.[49 ,50 ,51 ]IDH1 mutations are observed in older adolescents with high-grade gliomas.[48 ,51 ,52 ]

Pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups on the basis of epigenetic patterns (DNA methylation), with distinctive chromosome copy number gains/losses and gene mutations.[51 ,52 ] Two subgroups have identifiable recurrent mutations in H3F3A (the gene encoding histone 3.3), suggesting disrupted epigenetic regulatory mechanisms, with the most recognized subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34). The subgroups are the following:

H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brain stem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.[53 ] The 2016 WHO classification groups these cancers into a single entity, diffuse midline glioma, H3 K27M-mutant.[2 ]

H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 14-18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis.[51 ,52 ] The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome. Patients with H3F3A mutations are at high risk of treatment failure, but the prognosis is not as poor as it is for patients with K27M mutations.[52 ]

The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors.[54 ] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[49 ,50 ,51 ,54 ,55 ]

Pediatric glioblastoma multiforme patients whose tumors have IDH1 mutations are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors. IDH1-mutated cases often show TP53 mutations, MGMT promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP).[51 ,52 ] Pediatric patients with IDH1 mutations show a more favorable prognosis than do other pediatric glioblastoma multiforme patients.

A fourth group of pediatric glioblastoma multiforme patients identified by DNA methylation analysis are those lacking both histone mutations and IDH1 mutations. This is a heterogeneous group with higher rates of gene amplifications than other pediatric glioblastoma multiforme subtypes. The most commonly amplified genes are PDGFRA, EGFR, CCND/CDK, and MYC/MYCN.[51 ,52 ]

DNA methylation analysis of tumor tissue may identify pediatric tumors with a histologic diagnosis of glioblastoma multiforme, but with the molecular characteristics of other pediatric gliomas. For example, one study found that approximately 14% of patients with a diagnosis of glioblastoma multiforme had molecular characteristics that are associated with pleomorphic xanthoastrocytomas (e.g., high rates of BRAF V600E mutations).[52 ]

Infants and young children with a glioblastoma multiforme diagnosis appear to have tumors with distinctive molecular characteristics when compared with tumors of older children. One report that applied DNA methylation analysis to glioblastoma multiforme tumors observed a group of patients (representing approximately 7% of pediatric patients with a histologic diagnosis of glioblastoma multiforme) whose tumors had molecular characteristics consistent with low-grade gliomas. The median age for this group of patients was 1 year, and they showed a favorable prognosis (3-year overall survival, approximately 90%).[52 ] A second report investigated gene copy number gains and losses and mutation status of selected genes for glioblastoma multiforme tumors from children younger than 36 months.[56 ] Molecular alterations observed at appreciable rates in older children (e.g., K27M, CDKN2A loss, PDGFRA amplification, and TERT promoter mutations) were rare in the tumors of these young children, and novel abnormalities (e.g., loss of SNORD on chromosome 14q32) were observed in some cases.

Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 of 14 cases (57%).[33 ]

Prognosis

Low-grade astrocytomas

Low-grade astrocytomas (grade I [pilocytic] and grade II) have a relatively favorable prognosis, particularly for circumscribed, grade I lesions where complete excision may be possible.[10 ,11 ,57 ,58 ,59 ,60 ,61 ] Tumor spread, when it occurs, is usually by contiguous extension; dissemination to other CNS sites is uncommon, but does occur.[62 ,63 ] Although metastasis is uncommon, tumors may be of multifocal origin, especially when associated with NF1.

Unfavorable prognostic features for childhood low-grade astrocytomas include the following:[64 ,65 ,66 ]

Young age.

Diffuse histology, especially IDH-mutant.

Inability to obtain a complete resection.

Diencephalic syndrome.

Intracranial hypertension at initial presentation.

Metastases. When metastasis does occur, it is associated with a poorer long-term outcome.[67 ] However, it is increasingly evident that prognosis is largely dependent on specific molecular features integrated with standard pathological grouping.

Children with isolated optic nerve tumors have a better prognosis than those with lesions that involve the chiasm or that extend along the optic pathway.[68 ,69 ,70 ,71 ]; [72 ][Level of evidence: 3iiC] Children with NF1 also have a better prognosis, especially when the tumor is found in asymptomatic patients at the time of screening.[68 ,73 ]

High-grade astrocytomas

Although high-grade astrocytomas generally carry a poor prognosis in younger patients, those with anaplastic astrocytomas in whom a gross-total resection is possible may fare better,[59 ,74 ,75 ] as well as those with non-H3K27M-mutant tumors.

Molecular subtypes of pediatric glioblastoma multiforme show prognostic significance.[52 ] Patients whose tumors have histone K27M mutations have the poorest prognosis, with 3-year survival rates below 5%. Patients whose tumors have IDH1 mutations appear to have the most favorable prognosis among pediatric glioblastoma multiforme cases, while those with histone G34 mutations and those lacking both histone and IDH1 mutations have an intermediate prognosis (3-year OS, approximately 30%). In a multivariate analysis that included both molecular and clinical factors, the presence of gene amplifications and K27M mutations were associated with a poorer prognosis, while the presence of IDH1 mutations was associated with a more favorable prognosis.[52 ]

Treatment Option Overview for Childhood Astrocytomas

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1 ] Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with previously obtained results that assessed an existing therapy. Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. Information about ongoing National Cancer Institute (NCI)-supported clinical trials is available from the NCI website.

To determine and implement optimal treatment, planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Irradiation of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in that area to ensure optimal results.

Debilitating effects on growth and neurologic development have frequently been observed following radiation therapy, especially in younger children.[2 ,3 ,4 ] Also, there are other less-common complications of radiation therapy, including cerebrovascular accidents.[5 ] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with benign and malignant lesions.[6 ] Long-term management of these patients is complex and requires a multidisciplinary approach. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.

Treatment of Childhood Low-Grade Astrocytomas

To determine and implement optimal management, treatment is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.

In infants and young children, low-grade astrocytomas presenting in the hypothalamus make surgery difficult; consequently, biopsies are not always done. This is especially true in patients with neurofibromatosis type 1 (NF1).[1 ] When associated with NF1, tumors may be of multifocal origin.

For children with low-grade optic pathway astrocytomas, treatment options should be considered not only to improve survival but also to stabilize visual function.[2 ,3 ]

Observation, in the absence of any intervention, is an option for patients with NF1 or incidentally found, asymptomatic masses.[4 ,5 ,6 ,7 ] Spontaneous regressions of optic pathway gliomas have been reported in children with and without NF1.[8 ,9 ,10 ]

Cerebellum: Complete or near-complete removal can be obtained in 90% to 95% of patients with pilocytic tumors that occur in the cerebellum.[11 ]

Optic nerve: For children with isolated optic nerve lesions and progressive symptoms, complete surgical resection, while curative, generally results in blindness in the affected eye.

Midline structures (hypothalamus, thalamus, brain stem, and spinal cord): Low-grade astrocytomas that occur in midline structures can be aggressively resected, with resultant long-term disease control.[8 ,9 ,12 ,13 ]; [14 ][Level of evidence: 3iiiA] Such resection may result in significant neurologic sequelae, especially in children younger than 2 years at diagnosis.[8 ]; [15 ][Level of evidence: 3iC] Because of the infiltrative nature of some deep-seated lesions, extensive surgical resection may not be appropriate and biopsy only should be considered.[16 ][Level of evidence: 3iiiDiii]

Diffuse: Diffuse astrocytomas may be less amenable to total resection, and this may contribute to the poorer outcome.

In some low-grade astrocytomas, surgical resection can be performed more safely.[18 ] After resection, immediate (within 48 hours of resection per Children's Oncology Group [COG] criteria) postoperative magnetic resonance imaging is obtained. Surveillance scans are then obtained periodically for completely resected tumors, although the value following the initial 3- to 6-month postoperative period is uncertain.[19 ]; [20 ][Level of evidence: 3iiDiii]

Factors related to outcome for children with low-grade gliomas treated with surgery followed by observation were identified in a COG study that included 518 evaluable patients.[11 ] Overall outcome for the entire group was 78% progression-free survival (PFS) at 8 years and 96% overall survival (OS) at 8 years. The following factors were related to prognosis:[11 ]

Histology: Approximately three-fourths of patients had pilocytic astrocytoma; PFS and OS were superior for these patients when compared with children with nonpilocytic tumors.

Extent of resection: Patients with gross-total resection had 8-year PFS exceeding 90% and OS of 99%. By comparison, approximately one-half of patients with any degree of residual tumor (as assessed by operative report and by postoperative imaging) showed disease progression by 8 years, although OS exceeded 90%.[11 ]

The extent of resection necessary for cure is unknown because patients with microscopic and even gross residual tumor after surgery may experience long-term PFS without postoperative therapy.[1 ,6 ,11 ]

Age: Younger children (age <5 years) showed higher rates of tumor progression but there was no significant age effect for OS in multivariate analysis. In a retrospective review of a different series of pediatric patients, children younger than 1 year with low-grade glioma demonstrated an inferior PFS compared with children aged 1 year and older.[21 ]

The long-term functional outcome of cerebellar pilocytic astrocytomas is relatively favorable. Full-scale mean IQs of patients with low-grade gliomas treated with surgery alone are close to the normative population. However, long-term medical, psychological, and educational deficits may be present in these patients.[22 ]; [23 ,24 ][Level of evidence: 3iiiC]

Adjuvant therapy

Adjuvant therapy following complete resection of a low-grade glioma is generally not required unless there is a subsequent recurrence of disease. Treatment options for patients with incompletely resected tumor must be individualized and may include one or more of the following:

Observation.

Radiation therapy.

Second surgery.

Chemotherapy.

Targeted therapy (for subependymal giant cell astrocytomas).

A shunt or other cerebrospinal fluid diversion procedure may be needed.

Observation

In selected patients in whom a portion of the tumor has been resected, the patient may be observed without further disease-directed treatment, particularly if the pace of tumor regrowth is anticipated to be very slow. Approximately 50% of patients with less-than-gross total resection may have disease that remains progression-free at 5 to 8 years, supporting the observation strategy in selected patients.[11 ]

Radiation therapy

Radiation therapy is usually reserved until progressive disease is documented [17 ,25 ] and may be further delayed through the use of chemotherapy, a strategy that is commonly employed in young children.[26 ,27 ]

For children with low-grade gliomas for whom radiation therapy is indicated, approaches that contour the radiation to the tumor and avoid normal brain tissue (3-D conformal radiation therapy, intensity-modulated radiation therapy, stereotactic radiation therapy, and proton radiation therapy [charged-particle radiation therapy]) all appear effective and may potentially reduce the acute and long-term toxicities associated with these modalities.[28 ,29 ]; [30 ][Level of evidence: 3iDiii] Care must be taken in separating radiation-induced imaging changes from disease progression, which usually occurs during the first year after radiation, but may occur even after the first year, especially in patients with pilocytic astrocytomas.[31 ,32 ,33 ,34 ]; [35 ][Level of evidence: 2A]; [36 ][Level of evidence: 2C]; [37 ][Level of evidence: 3iiiDi]; [38 ][Level of evidence: 3iiiDii]; [16 ,39 ][Level of evidence: 3iiiDiii]

Radiation therapy results in long-term disease control for most children with chiasmatic and posterior pathway chiasmatic gliomas, but may also result in substantial intellectual and endocrinologic sequelae, cerebrovascular damage, late death, and possibly an increased risk of secondary tumors.[8 ,40 ,41 ,42 ,43 ]; [36 ][Level of evidence: 2C] A population-based study identified radiation therapy as the most significant risk factor associated with late mortality, although the patients who required radiation therapy may have reflected a higher-risk population.[43 ]

Radiation therapy and alkylating agents are used as last resorts for patients with NF1, given the theoretically heightened risk of inducing neurologic toxic effects and second malignancy in this population.[44 ] Children with NF1 may be at higher risk for radiation-associated secondary tumors and morbidity due to vascular changes.

Second surgery

An alternative to immediate radiation therapy is subtotal surgical resection, but it is unclear how many patients will have stable disease and for how long.[8 ]

Chemotherapy

Given the long-term side effects associated with radiation therapy, postoperative chemotherapy may be initially recommended.

Chemotherapy may result in objective tumor shrinkage and delay the need for radiation therapy in most patients.[26 ,27 ,45 ,46 ] Chemotherapy is also an option that may delay or avoid radiation therapy in adolescents with optic nerve pathway gliomas.[47 ][Level of evidence: 3iiDii] Chemotherapy has been shown to shrink tumors in children with hypothalamic gliomas and the diencephalic syndrome, resulting in weight gain in those who respond to treatment.[48 ]

The most widely used regimens to treat tumor progression or symptomatic nonresectable, low-grade gliomas are the following:

Carboplatin with or without vincristine.[26 ,27 ,49 ]; [50 ][Level of evidence: 3iiiDiii]

The COG reported the results of a randomized phase III trial (COG-A9952) that treated children younger than 10 years with low-grade chiasmatic/hypothalamic gliomas but without NF1 using one of two regimens: carboplatin and vincristine (CV) or TPCV. The 5-year event-free survival (EFS) rate was 39% ± 4% for the CV regimen and 52% ± 5% for the TPCV regimen. Toxicity rates between the two regimens were relatively comparable.[51 ] In the same study, children with NF1 were nonrandomly assigned to receive treatment with CV. The 5-year EFS for children with NF1 was markedly better, at 69% ± 4%, than it was for children without NF1 who received CV. In multivariate analysis, NF1 was an independent predictor of better EFS but not OS.[52 ]

Other chemotherapy approaches have been employed to treat children with progressive or symptomatic nonresectable, low-grade astrocytomas, including the following:

Multiagent, platinum-based regimens.[27 ,45 ,53 ]; [54 ][Level of evidence: 2Diii] Reported 5-year PFS rates have ranged from approximately 35% to 60% for children receiving platinum-based chemotherapy for optic pathway gliomas,[27 ,45 ] but most patients ultimately require further treatment. This is particularly true for children who initially present with hypothalamic/chiasmatic gliomas that have neuraxis dissemination.[55 ][Level of evidence: 3iiiDiii]

Among children receiving chemotherapy for optic pathway gliomas, those without NF1 have higher rates of disease progression than those with NF1, and infants have higher rates of disease progression than do children older than 1 year.[27 ,45 ,53 ,57 ] Whether vision is improved with chemotherapy is unclear.[57 ]; [60 ,61 ][Level of evidence: 3iiiC]

Targeted therapy

For children with symptomatic subependymal giant cell astrocytomas (SEGAs), agents that inhibit mammalian target of rapamycin (mTOR) (e.g., everolimus and sirolimus) have been studied.

Evidence (treatment of SEGA with mTOR inhibitor):

Small series have shown significant reductions in the size of these tumors after administration of everolimus or sirolimus, often eliminating the need for surgery.[62 ]; [63 ][Level of evidence: 2C]; [64 ][Level of evidence: 3iiDiv]; [65 ][Level of evidence: 3iiiC]

A multicenter, phase III, placebo-controlled trial of 117 patients confirmed these earlier findings; 35% of the patients in the everolimus group had at least a 50% reduction in the size of the SEGA, versus no reduction in the placebo group.[66 ][Level of evidence: 1iDiv]

In a study of patients who were treated with everolimus for 5 years, a reduction in the size of the mass was observed in about 50% of patients; in many cases, the reduction was sustained. These patients also had a reduction in seizure frequency.[67 ]

Treatment of Recurrent Childhood Low-Grade Astrocytomas

Childhood low-grade astrocytomas may recur many years after initial treatment.

An individual plan needs to be tailored based on the following:

Patient age.

Tumor location.

Prior treatment.

Recurrent disease is usually at the primary tumor site, although multifocal or widely disseminated disease to other intracranial sites and to the spinal leptomeninges has been documented.[68 ,69 ] Most children whose low-grade fibrillary astrocytomas recur will harbor low-grade lesions; however, transformation into a higher grade tumor is possible.[70 ] Surveillance imaging will frequently identify asymptomatic recurrences.[71 ]

At the time of recurrence, a complete evaluation to determine the extent of the relapse is indicated. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the following:

Initial tumor type.

Length of time between initial treatment and the reappearance of the mass lesion.

Patients with low-grade astrocytomas who relapse after being treated with surgery alone should be considered for another surgical resection.[72 ]

Radiation therapy

The rationale for the use of radiation therapy is essentially the same when utilized as first-line therapy or at the time of recurrence (refer to the Radiation therapy subsection of the Treatment of Newly Diagnosed Childhood Low-Grade Astrocytomas section of this summary). If the child has never received radiation therapy, local radiation therapy may be a treatment option, although chemotherapy in lieu of radiation may be considered, depending on the child's age and the extent and location of the tumor.[73 ][Level of evidence: 3iA]; [74 ][Level of evidence: 3iiiDi]

For children with low-grade gliomas for whom radiation therapy is indicated, conformal radiation therapy approaches appear effective and offer the potential for reducing the acute and long-term toxicities associated with this modality.[32 ,36 ]

Chemotherapy

If there is recurrence at an unresectable site that has been previously irradiated, chemotherapy should be considered.[75 ]

In patients previously treated with surgery and radiation therapy, chemotherapy should be considered. Chemotherapy may result in relatively long-term disease control.[27 ,76 ] Vinblastine alone, temozolomide alone, or temozolomide in combination with carboplatin and vincristine may be useful at the time of recurrence for children with low-grade gliomas.[27 ,57 ,58 ,76 ]

Targeted therapy with or without chemotherapy

Antitumor activity has also been observed for bevacizumab given in combination with irinotecan, which, in some cases, also results in clinical or visual improvement.[77 ]

Evidence (targeted therapy [bevacizumab]):

In a phase II study of bevacizumab plus irinotecan for children with recurrent low-grade gliomas, sustained partial response was observed in only two patients (5.7%), but the 6-month PFS was 85.4% (standard error [SE] ± 5.96%), and the 2-year PFS was 47.8% (SE ± 9.27%).[78 ]

Bevacizumab has also been employed for children with low-grade gliomas and symptomatic radiation-induced tumor enlargement; treatment with bevacizumab produced radiographic improvement (five of five patients) and allowed weaning off steroids (four of four patients).[81 ]

With the identification of BRAF mutations driving a significant proportion of low-grade gliomas, inhibition of various elements of this molecular pathway (MEK, BRAF V600E, etc.) are actively being tested in multiple ongoing clinical trials. In a preliminary report, this approach showed positive results in a phase I study of a MEK inhibitor in recurrent pediatric low-grade gliomas.[82 ] Other approaches include those investigating mTOR inhibitors (NCT01734512). Early results on the use of the BRAF V600E inhibitor dabrafenib, presented in abstract, demonstrated a 41% overall response rate (two complete responses and 11 partial responses) by central review in children with BRAF V600-mutant relapsed or refractory low-grade gliomas.[83 ]

Treatment options under clinical evaluation

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

ACNS1022 (NCT01553149) (Low-Dose or High-Dose Lenalidomide in Treating Younger Patients With Recurrent, Refractory, or Progressive Pilocytic Astrocytoma or Optic Pathway Glioma): This is a randomized phase II clinical trial comparing low-dose to high-dose lenalidomide to see how well each works in treating children with recurrent, refractory, or progressive juvenile pilocytic astrocytomas or optic nerve pathway gliomas. This clinical trial is based on results of a phase I study that observed tumor responses and long-term stable clinical disease for lenalidomide across a range of dose levels for children with recurrent low-grade gliomas.[84 ]

PBTC-029B (NCT01089101) (Selumetinib in Treating Young Patients With Recurrent or Refractory Low-Grade Glioma): This is a clinical trial to determine the side effects and the best dose of the MEK inhibitor selumetinib in children with low-grade astrocytoma (phase I component). Based on activity observed in the phase I component (now completed), the study has been modified to include phase II expansion cohorts for patients with pilocytic astrocytoma and other low-grade astrocytomas with BRAF genomic alterations and for NF1 patients with recurrent low-grade astrocytomas.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Laithier V, Grill J, Le Deley MC, et al.: Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy--results of the first French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21 (24): 4572-8, 2003.

Treatment of Childhood High-Grade Astrocytomas

To determine and implement optimal management, treatment of childhood high-grade astrocytomas is often guided by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors.

Treatment of Newly Diagnosed Childhood High-Grade Astrocytomas

Outcomes in high-grade gliomas occurring in childhood are often more favorable than that in adults. It is not clear whether this difference is caused by biologic variations in tumor characteristics, therapies used, tumor resectability, or other factors.[1 ]

The therapy for both children and adults with supratentorial high-grade astrocytoma includes surgery, radiation therapy, and chemotherapy.

The ability to obtain a complete resection is associated with a better prognosis.[2 ,3 ] Among patients treated with surgery, radiation therapy, and nitrosourea (lomustine)-based chemotherapy, 5-year progression-free survival was 19% ± 3%; survival was 40% in those who had total resections.[4 ] Similarly, in a trial of multiagent chemoradiation therapy and adjuvant chemotherapy in addition to valproic acid, 5-year event-free survival (EFS) was 13%, but for children with a complete resection of their tumor, the EFS was 48%.[5 ][Level of evidence: 2A]

Adjuvant therapy

Radiation therapy

Radiation therapy is routinely administered to a field that widely encompasses the entire tumor. The radiation therapy dose to the tumor bed is usually at least 54 Gy. Despite such therapy, overall survival rates remain poor. Similarly poor survival is seen in children with spinal cord primaries and children with thalamic high-grade gliomas (i.e., diffuse midline gliomas, H3K27M-mutant tumors) treated with radiation therapy.[6 ,7 ]; [8 ,9 ][Level of evidence: 3iiiA]

Chemotherapy

In one trial, children with glioblastoma who were treated on a prospective randomized trial with adjuvant lomustine, vincristine, and prednisone fared better than children treated with radiation therapy alone.[10 ] Furthermore, children who received lomustine in addition to temozolomide for subtotally-resected tumors, especially glioblastoma with methylated O6-methylguanine-DNA-methyltransferase (MGMT) overexpression, had a slightly improved outcome.[11 ] Patients with IDH1 mutations had improved 1-year overall survival (OS) (100%) when compared with IDH1-wildtype tumors (1-year OS, 81%), highlighting the potential importance of underlying biological characteristics.[12 ]

The use of temozolomide to treat glioblastoma was initially investigated in adults. In adults, the addition of temozolomide during and after radiation therapy resulted in improved 2-year EFS as compared with treatment with radiation therapy alone. Adult patients with glioblastoma with a MGMT promoter benefitted from temozolomide, whereas those who did not have a methylated MGMT promoter did not benefit from temozolomide.[13 ,14 ] The role of temozolomide given concurrently with radiation therapy for children with supratentorial high-grade glioma appears comparable to the outcome seen in children treated with nitrosourea-based therapy [15 ] and again demonstrated an EFS advantage for those children without MGMT overexpression.

Younger children may benefit from chemotherapy or consolidation with high-dose chemotherapy to delay, modify, or, in selected cases, obviate the need for radiation therapy.[16 ,17 ,18 ,19 ]

Treatment options under clinical evaluation

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium, or other entities. Information about National Cancer Institute (NCI)-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Recurrent Childhood High-Grade Astrocytomas

Most patients with high-grade astrocytomas or gliomas will eventually have tumor recurrence, usually within 3 years of original diagnosis, but some patients recur many years after initial treatment. Disease may recur at the primary tumor site, at the margin of the resection/radiation bed, or at noncontiguous central nervous system sites. Systemic relapse rarely occurs.

At the time of recurrence, a complete evaluation for extent of relapse is indicated for all malignant tumors. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities, such as secondary tumor and treatment-related brain necrosis, may be clinically indistinguishable from tumor recurrence.

Treatment options for recurrent childhood high-grade astrocytomas include the following:

Surgery.

High-dose chemotherapy with stem cell transplant (SCT).

Targeted therapy with a BRAF inhibitor, for patients with a BRAF V600E mutation.

Early-phase clinical trial.

The utility of surgical intervention must be individualized on the basis of the following:

Initial tumor type.

Length of time between initial treatment and the reappearance of the mass lesion.

Location of the recurrent tumor.

Consideration of therapeutics based on the requirement for fresh tumor tissue or to deliver therapy to the operative bed.

Patients for whom initial treatment fails may benefit from additional treatment, including entry into clinical trials of novel therapeutic approaches.[20 ] High-dose, marrow-ablative chemotherapy with hematopoietic SCT may be effective in a highly selected subset of patients with minimal residual disease at time of recurrence.[21 ]; [22 ][Level of evidence: 3iiiA] However, the results of previous clinical trials that tested various targeted and combination chemotherapies have largely failed to demonstrate convincing benefits for enrolled patients.[23 ,24 ,25 ]

Molecular targets for recurrent high-grade gliomas are limited. BRAF V600E mutations are present in a small subset of these patients, and a small number of cases have responded to BRAF inhibitors. A case report documented a complete response to the BRAF inhibitor vemurafenib in a patient with recurrent BRAF V600-mutated glioblastoma.[26 ] A phase I study reported in an abstract that eight children with progressive BRAF V600E high-grade gliomas were treated with dabrafenib and demonstrated three complete responses, three partial responses, and two progressive disease responses.[27 ]

Treatment options under clinical evaluation

The role of immune checkpoint inhibition in the treatment of children with recurrent high-grade astrocytoma is currently under study. Children with biallelic mismatch repair deficiency have a very high mutational burden and neoantigen expression and are at risk of developing a variety of cancers, including hematologic malignancies, gastrointestinal cancers, and brain tumors. The high mutation and neoantigen load has been correlated with improved response to immune checkpoint inhibition. Early case reports have demonstrated clinical and radiographic responses in children who are treated with an anti-programmed death-1 (anti-PD-1) inhibitor.[28 ]

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the COG, the Pediatric Brain Tumor Consortium, or other entities. Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Wisoff JH, Boyett JM, Berger MS, et al.: Current neurosurgical management and the impact of the extent of resection in the treatment of malignant gliomas of childhood: a report of the Children's Cancer Group trial no. CCG-945. J Neurosurg 89 (1): 52-9, 1998.

Changes to this Summary (09 / 22 / 2017)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Childhood Low-Grade Astrocytomas

Added Ahmed et al. as reference 13.

Added text about the APEC1621 (NCT03155620) trial as a treatment option under clinical evaluation for recurrent childhood low-grade astrocytomas.

Treatment of Childhood High-Grade Astrocytomas

Added text about the APEC1621 (NCT03155620) trial as a treatment option under clinical evaluation for recurrent childhood high-grade astrocytomas.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood astrocytomas. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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